Impact of Preexisting Mental Illness on All-Cause and Breast Cancer–Specific Mortality in Elderly Patients With Breast Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-21 Kristy Iglay; Melissa L. Santorelli; Kim M. Hirshfield; Jill M. Williams; George G. Rhoads; Yong Lin; Kitaw Demissie
PurposeLimited data are available on the survival of patients with breast cancer with preexisting mental illness, and elderly women are of special interest because they experience the highest incidence of breast cancer. Therefore, we compared all-cause and breast cancer–specific mortality for elderly patients with breast cancer with and without mental illness.MethodsA retrospective cohort study was conducted by using SEER-Medicare data, including 19,028 women ≥ 68 years of age who were diagnosed with stage I to IIIa breast cancer in the United States from 2005 to 2007. Patients were classified as having severe mental illness if an International Classification of Diseases, Ninth Edition, Clinical Modification code for bipolar disorder, schizophrenia, or other psychotic disorder was recorded on at least one inpatient or two outpatient claims during the 3 years before breast cancer diagnosis. Patients were followed for up to 5 years after breast cancer diagnosis to assess survival outcomes, which were then compared with those of patients without mental illness.ResultsNearly 3% of patients had preexisting severe mental illness. We observed a two-fold increase in the all-cause mortality hazard between patients with severe mental illness compared with those without mental illness after adjusting for age, income, race, ethnicity, geographic location, and marital status (adjusted hazard ratio, 2.19; 95% CI, 1.84 to 2.60). A 20% increase in breast cancer–specific mortality hazard was observed, but the association was not significant (adjusted hazard ratio, 1.20; 95% CI, 0.82 to 1.74). Patients with severe mental illness were more likely to be diagnosed with advanced breast cancer and aggressive tumor characteristics. They also had increased tobacco use and more comorbidities.ConclusionPatients with severe mental illness may need assistance with coordinating medical services.
Minimal Residual Disease Assessment in Lymphoma: Methods and Applications J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-21 Alex F. Herrera; Philippe Armand
Standard methods for disease response assessment in patients with lymphoma, including positron emission tomography and computed tomography scans, are imperfect. In other hematologic malignancies, particularly leukemias, the ability to detect minimal residual disease (MRD) is increasingly influencing treatment paradigms. However, in many subtypes of lymphoma, the application of MRD assessment techniques, like flow cytometry or polymerase chain reaction–based methods, has been challenging because of the absence of readily detected circulating disease or canonic chromosomal translocations. Newer MRD detection methods that use next-generation sequencing have yielded promising results in a number of lymphoma subtypes, fueling the hope that MRD detection may soon be applicable in clinical practice for most patients with lymphoma. MRD assessment can provide real-time information about tumor burden and response to therapy, noninvasive genomic profiling, and monitoring of clonal dynamics, allowing for many possible applications that could significantly affect the care of patients with lymphoma. Further validation of MRD assessment methods, including the incorporation of MRD assessment into clinical trials in patients with lymphoma, will be critical to determine how best to deploy MRD testing in routine practice and whether MRD assessment can ultimately bring us closer to the goal of personalized lymphoma care. In this review article, we describe the methods available for detecting MRD in patients with lymphoma and their relative advantages and disadvantages. We discuss preliminary results supporting the potential applications for MRD testing in the care of patients with lymphoma and strategies for including MRD assessment in lymphoma clinical trials.
Effect of Comorbidity on Prostate Cancer–Specific Mortality: A Prospective Observational Study J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-20 Prabhakar Rajan; Prasanna Sooriakumaran; Tommy Nyberg; Olof Akre; Stefan Carlsson; Lars Egevad; Gunnar Steineck; N. Peter Wiklund
PurposeTo determine the effect of comorbidity on prostate cancer (PCa)–specific mortality across treatment types.Patients and MethodsThese are the results of a population-based observational study in Sweden from 1998 to 2012 of 118,543 men who were diagnosed with PCa with a median follow-up of 8.3 years (interquartile range, 5.2 to 11.5 years) until death from PCa or other causes. Patients were categorized by patient characteristics (marital status, educational level) and tumor characteristics (serum prostate-specific antigen, tumor grade and clinical stage) and by treatment type (radical prostatectomy, radical radiotherapy, androgen deprivation therapy, and watchful waiting). Data were stratified by Charlson comorbidity index (0, 1, 2, or ≥ 3). Mortality from PCa and other causes and after stabilized inverse probability weighting adjustments for clinical patient and tumor characteristics and treatment type was determined. Kaplan-Meier estimates and Cox proportional hazards regression models were used to calculate hazard ratios.ResultsIn the complete unadjusted data set, we observed an effect of increased comorbidity on PCa-specific and other-cause mortality. After adjustments for patient and tumor characteristics, the effect of comorbidity on PCa-specific mortality was lost but maintained for other-cause mortality. After additional adjustment for treatment type, we again failed to observe an effect for comorbidity on PCa-specific mortality, although it was maintained for other-cause mortality.ConclusionThis large observational study suggests that comorbidity affects other cause–mortality but not PCa-specific– mortality after accounting for patient and tumor characteristics and treatment type. Regardless of radical treatment type (radical prostatectomy or radical radiotherapy), increasing comorbidity does not seem to significantly affect the risk of dying from PCa. Consequently, differences in oncologic outcomes that were observed in population-based comparative effectiveness studies of PCa treatments may not be a result of the varying distribution of comorbidity among treatment groups.
SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-20 Ruben A. Mesa; Jean-Jacques Kiladjian; John V. Catalano; Timothy Devos; Miklos Egyed; Andrzei Hellmann; Donal McLornan; Kazuya Shimoda; Elliott F. Winton; Wei Deng; Ronald L. Dubowy; Julia D. Maltzman; Francisco Cervantes; Jason Gotlib
PurposeWe evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis.Patients and MethodsPatients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements.ResultsA ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met (P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3).ConclusionIn JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.
Effect of Inpatient Palliative Care During Hematopoietic Stem-Cell Transplant on Psychological Distress 6 Months After Transplant: Results of a Randomized Clinical Trial J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-19 Areej El-Jawahri; Lara Traeger; Joseph A. Greer; Harry VanDusen; Sarah R. Fishman; Thomas W. LeBlanc; William F. Pirl; Vicki A. Jackson; Jason Telles; Alison Rhodes; Zhigang Li; Thomas R. Spitzer; Steven McAfee; Yi-Bin A. Chen; Jennifer S. Temel
Purpose Inpatient palliative care integrated with transplant care improves patients’ quality of life (QOL) and symptom burden during hematopoietic stem-cell transplant (HCT). We assessed patients’ mood, post-traumatic stress disorder (PTSD) symptoms, and QOL 6 months post-transplant. Methods We randomly assigned 160 patients with hematologic malignancies who underwent autologous or allogeneic HCT to inpatient palliative care integrated with transplant care (n = 81) or transplant care alone (n = 79). At baseline and 6 months post-transplant, we assessed mood, PTSD symptoms, and QOL with the Hospital Anxiety and Depression Scale and Patient Health Questionnaire, PTSD checklist, and Functional Assessment of Cancer Therapy-Bone Marrow Transplant. To assess symptom burden during HCT, we used the Edmonton Symptom Assessment Scale. We used analysis of covariance while controlling for baseline values to examine intervention effects and conducted causal mediation analyses to examine whether symptom burden or mood during HCT mediated the effect of the intervention on 6-month outcomes. Results We enrolled 160 (86%) of 186 potentially eligible patients between August 2014 and January 2016. At 6 months post-transplant, intervention participants reported lower depression symptoms on the Hospital Anxiety and Depression Scale and Patient Health Questionnaire (adjusted mean difference, −1.21 [95% CI, −2.26 to −0.16; P = .024] and −1.63 [95% CI, −3.08 to −0.19; P = .027], respectively) and lower PTSD symptoms (adjusted mean difference, −4.02; 95% CI, −7.18 to −0.86; P = .013), but no difference in QOL or anxiety. Symptom burden and anxiety during HCT hospitalization partially mediated the effect of the intervention on depression and PTSD at 6 months post-transplant. Conclusion Inpatient palliative care integrated with transplant care leads to improvements in depression and PTSD symptoms at 6 months post-transplant. Reduction in symptom burden and anxiety during HCT partially accounts for the effect of the intervention on these outcomes.
Succeeding in Breaking the R-CHOP Ceiling in DLBCL: Learning From Negative Trials J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-19 Andre Goy
The introduction of anthracyclines into the first-generation regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 1976 resulted in a 10-year overall survival of around 20%.1 Despite being promising in phase II testing, more complex second- and third-generation regimens did not supersede CHOP in a large phase III trial.2 A decade later, the addition of the anti-CD20 monoclonal antibody (mAb) rituximab became the first improvement over CHOP,3 initially shown in patients older than age 60 years, but rapidly confirmed for all patients with diffuse large B-cell lymphoma (DLBCL), setting a new standard that is still valid today. With six cycles of rituximab plus CHOP (R-CHOP) given once every 21 days, more than half of patients can be cured, and in those who are event-free at 24 months, the subsequent survival is equivalent to that of the age- and sex-matched general population.4 However, about 10% to 20% of patients do not respond to R-CHOP induction (ie, primary refractory), and 30% to 40% relapse after achieving complete remission (CR). Overall, 80% of all chemoimmunotherapy failures occur early (within 12 to 18 months of diagnosis), and patients then often experience a poor outcome,5 even with high-dose therapy followed by autologous stem-cell transplantation.6 These observations have formed the basis of numerous attempts to improve on R-CHOP, which have generally been unsuccessful thus far.
Preexisting Cardiovascular Risk and Subsequent Heart Failure Among Non-Hodgkin Lymphoma Survivors J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-18 Talya Salz; Emily C. Zabor; Peter de Nully Brown; Susanne Oksberg Dalton; Nirupa J. Raghunathan; Matthew J. Matasar; Richard Steingart; Andrew J. Vickers; Peter Svenssen Munksgaard; Kevin C. Oeffinger; Christoffer Johansen
Purpose The use of anthracycline chemotherapy is associated with heart failure (HF) among survivors of non-Hodgkin lymphoma (NHL). We aimed to understand the contribution of preexisting cardiovascular risk factors to HF risk among NHL survivors. Methods Using Danish registries, we identified adults diagnosed with aggressive NHL from 2000 to 2010 and sex- and age-matched general-population controls. We assessed HF from 9 months after diagnosis through 2012. We used Cox regression analysis to assess differences in risk for HF between survivors and general population controls. Among survivors only, preexisting cardiovascular factors (hypertension, dyslipidemia, and diabetes) and preexisting cardiovascular disease were ascertained. We used multivariable Cox regression to model the association of preexisting cardiovascular conditions on subsequent HF. Results Among 2,508 survivors of NHL and 7,399 controls, there was a 42% increased risk of HF among survivors compared with general population controls (hazard ratio [HR], 1.42; 95% CI, 1.07 to 1.88). Among survivors (median age at diagnosis, 62 years; 56% male), 115 were diagnosed with HF during follow-up (median years of follow-up, 2.5). Before NHL diagnosis, 39% had ≥ 1 cardiovascular risk factor; 92% of survivors were treated with anthracycline-containing regimens. In multivariable analysis, intrinsic heart disease diagnosed before lymphoma was associated with increased risk of HF (HR, 2.71; 95% CI, 1.15 to 6.36), whereas preexisting vascular disease had no association with HF (P > .05). Survivors with cardiovascular risk factors had an increased risk of HF compared with those with none (for 1 v 0 cardiovascular risk factors: HR, 1.63; 95% CI, 1.07 to 2.47; for ≥ 2 v 0 cardiovascular risk factors: HR, 2.86; 95% CI, 1.56 to 5.23; joint P < .01). Conclusion In a large, population-based cohort of NHL survivors, preexisting cardiovascular conditions were associated with increased risk of HF. Preventive approaches should take baseline cardiovascular health into account.
Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-15 Mario Sznol; Pier Francesco Ferrucci; David Hogg; Michael B. Atkins; Pascal Wolter; Massimo Guidoboni; Celeste Lebbé; John M. Kirkwood; Jacob Schachter; Gregory A. Daniels; Jessica Hassel; Jonathan Cebon; Winald Gerritsen; Victoria Atkinson; Luc Thomas; John McCaffrey; Derek Power; Dana Walker; Rafia Bhore; Joel Jiang; F. Stephen Hodi; Jedd D. Wolchok
PurposeThe addition of nivolumab (anti–programmed death-1 antibody) to ipilimumab (anti–cytotoxic T-cell lymphocyte–associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen.MethodsThis retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome.ResultsAmong 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy.ConclusionFrequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.
Effective Physical Activity Promotion to Survivors of Cancer Is Likely to Be Home Based and to Require Oncologist Participation J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-15 Sarah J. Hardcastle; Paul A. Cohen
Cancer is a leading cause of disease burden worldwide.1 Public health practitioners and researchers in behavioral medicine recognize the need to find effective physical activity interventions to curb the growth in inactivity and prevent chronic illness in survivors of cancer.2,3 Physical activity prevents cardiovascular disease4,5 and may reduce the risk of cancer recurrence,6-9 yet few survivors meet current physical activity guidelines of 30 minutes per day of moderate-intensity exercise.10 There has been a proliferation of trial interventions, yet only a minority of survivors of cancer receive physical activity advice or referrals to exercise programs as a part of routine care.11-13
Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-13 Kaoru Kubota; Hiroshige Yoshioka; Fumihiro Oshita; Toyoaki Hida; Kiyotaka Yoh; Hidetoshi Hayashi; Terufumi Kato; Hiroyasu Kaneda; Kazuhiko Yamada; Hiroshi Tanaka; Yukito Ichinose; Keunchil Park; Eun Kyung Cho; Kyung-Hee Lee; Chih-Bin Lin; James Chih-Hsin Yang; Kaori Hara; Takayuki Asato; Kazuhiko Nakagawa
Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung cancer. Patients and Methods Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m2 IV and carboplatin area under the concentration-time curve 6 mg/mL ⋅ min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months (P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% (P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade ≥ 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung cancer.
Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-13 Robert J. Motzer; Naomi B. Haas; Frede Donskov; Marine Gross-Goupil; Sergei Varlamov; Evgeny Kopyltsov; Jae Lyun Lee; Bohuslav Melichar; Brian I. Rini; Toni K. Choueiri; Milada Zemanova; Lori A. Wood; M. Neil Reaume; Arnulf Stenzl; Simon Chowdhury; Ho Yeong Lim; Ray McDermott; Agnieszka Michael; Weichao Bao; Marlene J. Carrasco-Alfonso; Paola Aimone; Maurizio Voi; Christian Doehn; Paul Russo; Cora N. Sternberg; on behalf of the PROTECT investigators
Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT800mg) and safety. Results The primary analysis results of DFS ITT600mg favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT800mg (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT600mg yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting.
Prognostic Model to Predict Post-Autologous Stem-Cell Transplantation Outcomes in Classical Hodgkin Lymphoma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-12 Fong Chun Chan; Anja Mottok; Alina S. Gerrie; Maryse Power; Marcel Nijland; Arjan Diepstra; Anke van den Berg; Peter Kamper; Francesco d’Amore; Alexander Lindholm d’Amore; Stephen Hamilton-Dutoit; Kerry J. Savage; Sohrab P. Shah; Joseph M. Connors; Randy D. Gascoyne; David W. Scott; Christian Steidl
PurposeOur aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT).Materials and MethodsWe performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression–based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation.ResultsGene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry.ConclusionWe have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography–guided response assessment and the evolving cHL treatment landscape.
Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-11 Federica Grosso; Nicola Steele; Silvia Novello; Anna K. Nowak; Sanjay Popat; Laurent Greillier; Thomas John; Natasha B. Leighl; Martin Reck; Paul Taylor; David Planchard; Jens Benn Sørensen; Mark A. Socinski; Ute von Wangenheim; Arsène Bienvenu Loembé; José Barrueco; Nassim Morsli; Giorgio Scagliotti
Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.
Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children’s Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children’s Oncology Group J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-11 Allison F. O’Neill; Alexander J. Towbin; Mark D. Krailo; Caihong Xia; Yun Gao; M. Beth McCarville; Rebecka L. Meyers; Eugene D. McGahren; Greg M. Tiao; Stephen P. Dunn; Max R. Langham Jr; Christopher B. Weldon; Milton J. Finegold; Sarangarajan Ranganathan; Wayne L. Furman; Marcio Malogolowkin; Carlos Rodriguez-Galindo; Howard M. Katzenstein
Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Children’s Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event (P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis.
Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population-Based Cohort Study J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-11 Lene Sofie Granfeldt Østgård; Mette Nørgaard; Bruno C. Medeiros; Lone Smidstrup Friis; Claudia Schoellkopf; Marianne Tang Severinsen; Claus Werenberg Marcher; Jan Maxwell Nørgaard
Purpose Previous US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or income and clinical characteristics, treatment, and outcome in AML. Methods To investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios [HRs]) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers. Results Of 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27). Conclusion In a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients.
Patient-Clinician Communication: American Society of Clinical Oncology Consensus Guideline J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-11 Timothy Gilligan; Nessa Coyle; Richard M. Frankel; Donna L. Berry; Kari Bohlke; Ronald M. Epstein; Esme Finlay; Vicki A. Jackson; Christopher S. Lathan; Charles L. Loprinzi; Lynne H. Nguyen; Carole Seigel; Walter F. Baile
Purpose To provide guidance to oncology clinicians on how to use effective communication to optimize the patient-clinician relationship, patient and clinician well-being, and family well-being. Methods ASCO convened a multidisciplinary panel of medical oncology, psychiatry, nursing, hospice and palliative medicine, communication skills, health disparities, and advocacy experts to produce recommendations. Guideline development involved a systematic review of the literature and a formal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, and randomized controlled trials published from 2006 through October 1, 2016. Results The systematic review included 47 publications. With the exception of clinician training in communication skills, evidence for many of the clinical questions was limited. Draft recommendations underwent two rounds of consensus voting before being finalized. Recommendations In addition to providing guidance regarding core communication skills and tasks that apply across the continuum of cancer care, recommendations address specific topics, such as discussion of goals of care and prognosis, treatment selection, end-of-life care, facilitating family involvement in care, and clinician training in communication skills. Recommendations are accompanied by suggested strategies for implementation. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki.
Changes in Insurance Coverage and Stage at Diagnosis Among Nonelderly Patients With Cancer After the Affordable Care Act J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-08 Ahmedin Jemal; Chun Chieh Lin; Amy J. Davidoff; Xuesong Han
Purpose To examine change in the percent uninsured and early-stage diagnosis among nonelderly patients with newly diagnosed cancer after the Affordable Care Act (ACA). Patients and Methods By using the National Cancer Data Base, we estimated absolute change (APC) and relative change in percent uninsured among patients with newly diagnosed cancer age 18 to 64 years between 2011 to the third quarter of 2013 (pre-ACA implementation) and the second to fourth quarter of 2014 (post-ACA) in Medicaid expansion and nonexpansion states by family income level. We also examined demographics-adjusted difference in differences in APC between Medicaid expansion and nonexpansion states. We similarly examined changes in insurance and early-stage diagnosis for the 15 leading cancers in men and women (top 17 cancers total). Results Between the pre-ACA and post-ACA periods, percent uninsured among patients with newly diagnosed cancer decreased in all income categories in both Medicaid expansion and nonexpansion states. However, the decrease was largest in low-income patients who resided in expansion states (9.6% to 3.6%; APC, −6.0%; 95% CI, −6.5% to −5.5%) versus their counterparts who resided in nonexpansion states (14.7% to 13.3%; APC, −1.4%; 95% CI, −2.0% to −0.7%), with an adjusted difference in differences of −3.3 (95% CI, −4.0 to −2.5). By cancer type, the largest decrease in percent uninsured occurred in patients with smoking- or infection-related cancers. A small but statistically significant shift was found toward early-stage diagnosis for colorectal, lung, female breast, and pancreatic cancer and melanoma in patients who resided in expansion states. Conclusion Percent uninsured among nonelderly patients with newly diagnosed cancer declined substantially after the ACA, especially among low-income people who resided in Medicaid expansion states. A trend toward early-stage diagnosis for select cancers in expansion states also was found. These results reinforce the importance of policies directed at providing affordable coverage to low-income, vulnerable populations.
Metastatic Lymph Node Burden and Survival in Oral Cavity Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-07 Allen S. Ho; Sungjin Kim; Mourad Tighiouart; Cynthia Gudino; Alain Mita; Kevin S. Scher; Anna Laury; Ravi Prasad; Stephen L. Shiao; Jennifer E. Van Eyk; Zachary S. Zumsteg
Purpose Current staging systems for oral cavity cancers incorporate lymph node (LN) size and laterality, but place less weight on the total number of positive metastatic nodes. We investigated the independent impact of numerical metastatic LN burden on survival. Methods Adult patients with oral cavity squamous cell carcinoma undergoing upfront surgical resection for curative intent were identified in the National Cancer Data Base between 2004 and 2013. A neck dissection of a minimum of 10 LNs was required. Multivariable models were constructed to assess the association between the number of metastatic LNs and survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Results Overall, 14,554 patients met inclusion criteria (7,906 N0 patients; 6,648 node-positive patients). Mortality risk escalated continuously with increasing number of metastatic nodes without plateau, with the effect most pronounced with up to four LNs (HR, 1.34; 95% CI, 1.29 to 1.39; P < .001). Extranodal extension (HR, 1.41; 95% CI, 1.20 to 1.65; P < .001) and lower neck involvement (HR, 1.16; 95% CI, 1.06 to 1.27; P < .001) also predicted increased mortality. Increasing number of nodes examined was associated with improved survival, plateauing at 35 LNs (HR, 0.98; 95% CI, 0.98 to 0.99; P < .001). In multivariable models accounting for the number of metastatic nodes, contralateral LN involvement (N2c status) and LN size were not associated with mortality. A novel nodal staging system derived by recursive partitioning analysis exhibited greater concordance than the American Joint Committee on Cancer (8th edition) system. Conclusion The number of metastatic nodes is a critical predictor of oral cavity cancer mortality, eclipsing other features such as LN size and contralaterality in prognostic value. More robust incorporation of numerical metastatic LN burden may augment staging and better inform adjuvant treatment decisions.
Pembrolizumab in Programmed Death Ligand 1–Positive Endometrial Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-07 Federica Tomao; Pierluigi Benedetti Panici; Silverio Tomao
In the article by Ott et al,1 the aim of the study, KEYNOTE-028 (NCT02054806), was to evaluate the activity and safety profile of pembrolizumab in patients with heavily pretreated advanced endometrial cancer (EC), a subgroup with a poor prognosis. This article deserves some consideration to give the study proper meaning. Unfortunately, it is a small study, as are others that explore the activity of different agents in advanced and metastatic EC. Of the 75 patients evaluated for programmed death ligand 1 expression, 36 (48%) had positive tumors. According to eligibility criteria, up to 12 patients were excluded; moreover, another woman was excluded for lack of post-baseline assessment, and three received no assessment at the time of the data cutoff. The study design stated that sarcomas should be excluded; in our opinion, even a patient with a carcinosarcoma should have been excluded to have a more homogeneous group for this investigation. For the same reason, the two patients who received adjuvant radiotherapy should have been excluded. Therefore, only 17 patients were eligible by clinical assessment—certainly too few to answer to the question about clinical activity of pembrolizumab in patients with programmed death ligand 1–positive EC.
Reply to F. Tomao et al J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-07 Patrick A. Ott; Jean-Charles Soria
We thank Tomao et al1 for their comment on our study.2 We fully agree with the authors’ assessment that the number of patients who were treated with pembrolizumab in our trial is small and, therefore, that it is premature to recommend treatment with pembrolizumab as monotherapy for patients with pretreated advanced endometrial cancer. As we state in the conclusion of our paper, and in agreement with the authors’ suggestions, additional testing of predictive biomarkers (as done in the KEYNOTE-158 trial) and development of pembrolizumab as a partnering agent in a combinatorial approach may be needed for this patient population.2 We note that, when the KEYNOTE-028 study was designed, antitumor activity with programmed death 1– or programmed death ligand 1 (PD-L1)–directed monoclonal antibodies had been reported in a small number of tumor types, including melanoma, non–small-cell lung cancer, and renal cell cancer, but the clinical efficacy of this novel immune checkpoint therapy was unknown in many other malignancies.3,4 Thus, the study was designed as a signal-finding study with objective response rate as the primary end point, and enrollment was limited to patients with PD-L1–positive tumors on the basis of early evidence of tumor PD-L1 expression as a potentially useful predictive biomarker.4 As the authors indicate, the study was not powered to evaluate overall survival, nor was it randomized to compare with another agent and formally establish an improvement in overall survival. Nevertheless, consistent with other tumor cohorts assessed in KEYNOTE-028, our study provided, to our knowledge, the first evidence of durable clinical activity for a subset of patients with heavily pretreated advanced endometrial cancer who were treated with pembrolizumab.
Starting Dose of Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-05 Kim A. Reiss; Shun Yu; Ronac Mamtani; Rajni Mehta; Kathryn D’Addeo; E. Paul Wileyto; Tamar H. Taddei; David E. Kaplan
Purpose Sorafenib is currently the only Food and Drug Administration–approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D (P < .001), higher Model for End-Stage Liver Disease Sodium scores (P < .001), higher Child-Turcotte-Pugh scores (P < .001), and higher Cirrhosis Comorbidity Index scores (P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HRadj], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin (P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.
Thalidomide: Rebirth of a Gestational Antiemetic? J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-05 Kathryn J. Ruddy; Rudolph M. Navari; Charles L. Loprinzi
Chemotherapy-associated nausea and vomiting impairs the quality of life in many patients with cancer. Several clinical trials have demonstrated that corticosteroids, serotonin (5-HT3) receptor antagonists (RAs), neurokinin 1 (NK1) RAs, and olanzapine have markedly improved, but have not totally resolved, this vexing problem. To further reduce chemotherapy-induced nausea and vomiting, basic research and clinical trials are currently underway.
Randomized Phase II Study of R-CHOP With or Without Bortezomib in Previously Untreated Patients With Non–Germinal Center B-Cell–Like Diffuse Large B-Cell Lymphoma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-01 John P. Leonard; Kathryn S. Kolibaba; James A. Reeves; Anil Tulpule; Ian W. Flinn; Tatjana Kolevska; Robert Robles; Christopher R. Flowers; Robert Collins; Nicholas J. DiBella; Steven W. Papish; Parameswaran Venugopal; Andrew Horodner; Amir Tabatabai; Julio Hajdenberg; Jaehong Park; Rachel Neuwirth; George Mulligan; Kaveri Suryanarayan; Dixie-Lee Esseltine; Sven de Vos
Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non–germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2 intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP). Results After a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP (P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%). Conclusion Outcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.
Activity of Eribulin in Patients With Advanced Liposarcoma Demonstrated in a Subgroup Analysis From a Randomized Phase III Study of Eribulin Versus Dacarbazine J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-30 George D. Demetri; Patrick Schöffski; Giovanni Grignani; Jean-Yves Blay; Robert G. Maki; Brian A. Van Tine; Thierry Alcindor; Robin L. Jones; David R. D’Adamo; Matthew Guo; Sant Chawla
Purpose A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma showed a significant improvement in overall survival (OS) for the eribulin arm, with a manageable toxicity profile. We now report the histology-specific subgroup analysis of the efficacy and safety of eribulin compared with dacarbazine in patients with LPS, an independently randomized stratified subgroup of this phase III trial. Methods Patients ≥ 18 years with advanced or metastatic dedifferentiated, myxoid/round cell, or pleomorphic LPS incurable by surgery or radiotherapy were included. Patients with Eastern Cooperative Oncology Group performance status ≤ 2 and two or more prior systemic treatment regimens, including one with anthracycline, were randomly assigned 1:1 to receive eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850, 1,000, or 1,200 mg/m2 intravenously on day 1) every 21 days. OS, progression-free survival (PFS), and safety were analyzed. Results In the LPS subgroup, OS was significantly improved: 15.6 versus 8.4 months (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < .001) with eribulin versus dacarbazine, respectively. Longer OS with eribulin was observed in all LPS histologic subtypes and in all geographic regions evaluated. PFS was also improved with eribulin versus dacarbazine (2.9 v 1.7 months, respectively; hazard ratio, 0.52; 95% CI, 0.35 to 0.78; P = .0015). Adverse events were similar between arms. Conclusion In patients with previously treated LPS, eribulin was associated with significantly superior OS and PFS compared with dacarbazine. Eribulin represents an important treatment option for patients with LPS, a sarcoma subtype for which limited effective systemic treatments are available. Further studies are justified to explore the role of eribulin in earlier lines of therapy as well as in combination with other agents.
Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non–Small-Cell Lung Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-30 Ramaswamy Govindan; Aleksandra Szczesna; Myung-Ju Ahn; Claus-Peter Schneider; Pablo Fernando Gonzalez Mella; Fabrice Barlesi; Baohui Han; Doina Elena Ganea; Joachim Von Pawel; Vladimir Vladimirov; Natalia Fadeeva; Ki Hyeong Lee; Takayasu Kurata; Li Zhang; Tomohide Tamura; Pieter E. Postmus; Jacek Jassem; Kenneth O’Byrne; Justin Kopit; Mingshun Li; Marina Tschaika; Martin Reck
Purpose Patients with squamous non–small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.
Efficacy of Thalidomide in Preventing Delayed Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Trial (CLOG1302 study) J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-30 Lingyun Zhang; Xiujuan Qu; Yuee Teng; Jing Shi; Ping Yu; Tao Sun; Jingyan Wang; Zhitu Zhu; Xiuna Zhang; Mingfang Zhao; Jing Liu; Bo Jin; Ying Luo; Zan Teng; Yuyang Dong; Fugang Wen; Yuzhi An; Caijun Yuan; Tiejun Chen; Lizhong Zhou; Ying Chen; Jian Zhang; Zhenghua Wang; Jinglei Qu; Feng Jin; Jingdong Zhang; Xiuhua Jin; Xiaodong Xie; Jun Wang; Li Man; Lingyu Fu; Yunpeng Liu
Purpose We examined the efficacy and safety of thalidomide (THD) for the prevention of delayed nausea and vomiting in patients who received highly emetogenic chemotherapy (HEC). Patients and Methods In a randomized, double-blind, active-controlled, phase III trial, chemotherapy-naive patients with cancer who were scheduled to receive HEC that contained cisplatin or cyclophosphamide-doxorubicin/epirubincin ≥ 50 mg/m2 regimens were randomly assigned to a THD group (100 mg twice daily on days 1 to 5) or placebo group, both with palonosetron (0.25 mg on day 1) and dexamethasone (12 mg on day 1; 8 mg on days 2 to 4). Primary end point was complete response to vomiting—no emesis or use of rescue medication—in the delayed phase (25 to 120 h). Nausea and anorexia on days 1 to 5 were evaluated by the 4-point Likert scale (0, no symptoms; 3, severe). Quality of life was assessed by the European Organization for Research and Treatment of Cancer QLQ-C30 version 3 questionnaire on days −1 and 6. Results Of 656 patients, 638 were evaluable: 317 in the THD group and 321 in the control group. Compared with placebo, delayed and overall (0 to 120 h) complete response rates to vomiting were significantly higher with THD: 76.9% versus 61.7% (P < .001) and 66.1% versus 53.3% (P = .001), respectively. Rates of no nausea were also higher in the THD group (delayed: 47.3% v 33.3%; P < .001; overall: 41% v 29.6%; P = .003), and mean scores of anorexia were lower overall (0.44 ± 0.717 v 0.64 ± 0.844; P = .003). Adverse effects were mild to moderate. The THD group had increased sedation, dizziness, constipation, and dry mouth, but experienced better quality of life after chemotherapy. Conclusion Thalidomide combined with palonosetron and dexamethasone significantly improved HEC-induced delayed nausea and vomiting prevention in chemotherapy-naive patients.
First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-30 Matthew P. Goetz; Vera J. Suman; Joel M. Reid; Don W. Northfelt; Michael A. Mahr; Andrew T. Ralya; Mary Kuffel; Sarah A. Buhrow; Stephanie L. Safgren; Renee M. McGovern; John Black; Travis Dockter; Tufia Haddad; Charles Erlichman; Alex A. Adjei; Dan Visscher; Zachary R. Chalmers; Garrett Frampton; Benjamin R. Kipp; Minetta C. Liu; John R. Hawse; James H. Doroshow; Jerry M. Collins; Howard Streicher; Matthew M. Ames; James N. Ingle
Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor–positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients (PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival (v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations (PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations (ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.
Practice Makes Perfect: The Rest of the Story in Testicular Cancer as a Model Curable Neoplasm J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-30 Torgrim Tandstad; Christian K. Kollmannsberger; Bruce J. Roth; Claudio Jeldres; Silke Gillessen; Karim Fizazi; Siamak Daneshmand; William T. Lowrance; Nasser H. Hanna; Costantine Albany; Richard Foster; Gabriella Cohn Cedermark; Darren R. Feldman; Thomas Powles; Mark A. Lewis; Peter Scott Grimison; Douglas Bank; Christopher Porter; Peter Albers; Maria De Santis; Sandy Srinivas; George J. Bosl; Craig R. Nichols
The story of the successful management of disseminated testicular cancer (TC) is well known and is listed among the American Society of Clinical Oncology’s top five accomplishments in cancer medicine in the last 50 years.1,2 Using the development of highly active systemic chemotherapy as a backbone, global outcomes achieved in experienced centers or collaborative groups are unparalleled. Now, many patients presenting with TC receive no therapy beyond orchiectomy. Those who do present with or develop more advanced disease are most often rendered disease free with inexpensive, relatively brief treatments. More than 95% of all patients are cured and most enjoy high-quality, long-term survivorship.
Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography After Concurrent Chemoradiotherapy in Locally Advanced Head-and-Neck Squamous Cell Cancer: The ECLYPS Study J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-30 Tim Van den Wyngaert; Nils Helsen; Laurens Carp; Sara Hakim; Michel J. Martens; Isabel Hutsebaut; Philip R. Debruyne; Annelies L.M. Maes; Joost van Dinther; Carl G. Van Laer; Otto S. Hoekstra; Remco De Bree; Sabine A.E. Meersschout; Olivier Lenssen; Jan B. Vermorken; Danielle Van den Weyngaert; Sigrid Stroobants; on behalf of the ECLYPS investigators
Purpose To assess the standardized implementation and reporting of surveillance [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan of the neck in locoregionally advanced head-and-neck squamous cell carcinoma (LAHNSCC) after concurrent chemoradiotherapy (CCRT). Patients and Methods We performed a prospective multicenter study of FDG-PET/CT scanning 12 weeks after CCRT in newly diagnosed patients with LAHNSCC (stage IVa/b) that used standardized reconstruction and Hopkins reporting criteria. The reference standard was histology or > 12 months of clinical follow-up. The primary outcome measure was the negative predictive value (NPV) of FDG-PET/CT scans and other supporting diagnostic test characteristics, including time dependency with increasing follow-up time. Results Of 152 patients, 125 had adequate primary tumor control after CCRT and entered follow-up (median, 20.4 months). Twenty-three (18.4%) had residual neck disease. Overall, NPV was 92.1% (95% CI, 86.9% to 95.3%; null hypothesis: NPV = 85%; P = .012) with sensitivity of 65.2% (95% CI, 44.9% to 81.2%), specificity of 91.2% (95% CI, 84.1% to 95.3%), positive predictive value of 62.5% (95% CI, 45.5% to 76.9%), and accuracy of 86.4% (95% CI, 79.3% to 91.3%). Sensitivity was time dependent and high for residual disease manifesting up to 9 months after imaging but lower (59.7%) for disease detected up to 12 months after imaging. Standardized reporting criteria reduced the number of equivocal reports (95% CI for the difference, 2.6% to 15.0%; P = .003). Test characteristics were not improved with the addition of lymph node CT morphology criteria. Conclusion FDG-PET/CT surveillance using Hopkins criteria 12 weeks after CCRT is reliable in LAHNSCC except for late manifesting residual disease, which may require an additional surveillance scan at 1 year after CCRT to be detected.
Endoxifen: The End, or Are We at the Beginning? J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-30 V. Craig Jordan
Tamoxifen had its origins as a failed morning-after contraceptive that became the first successful targeted treatment in cancer.1-3 Tamoxifen dominated the antiestrogenic treatment of metastatic breast cancer (MBC) for 30 years and went forward as the only candidate for long-term adjuvant antiestrogen treatment.2,3 As a result of decades of clinical testing, tamoxifen was the only candidate in the pioneering of breast cancer chemoprevention.4 There was a reason for this. Try as they may, medicinal chemists in the pharmaceutical industry could not improve on tamoxifen for the treatment of MBC. The list of nonsteroidal antiestrogens evaluated to treat MBC is long: nafoxidine, trioxifene, keoxifene (reinvented and renamed raloxifene to treat osteoporosis5), toremifene, droloxifene, and arzoxifene.6,7 As a result, an alternative strategy for antiestrogen therapy was advanced. Specific inhibitors of CYP19, the aromatase enzyme, were investigated. In the 1970s, Dr Angela Brodie, the mother of aromatase inhibitors (AIs), used translational research to show that a clinically useful drug was possible.8 The pharmaceutical industry again struggled for a decade to find suitable oral candidates to compete with tamoxifen. Today, there are three established agents that dominate breast cancer treatment and prevention for postmenopausal women: anastrozole, exemestane, and letrozole. So it comes as some surprise that a phase I study of endoxifen, a tamoxifen metabolite, was successfully completed in patients with endocrine refractory breast cancer.
Erratum J. Clin. Oncol. (IF 24.008) Pub Date : 2017-09-01
The July 1, 2017, article by Willmann et al entitled “Ultrasound Molecular Imaging With BR55 in Patients With Breast and Ovarian Lesions: First-in-Human Results” (J Clin Oncol 35:2133-2140, 2017) contained an error in the author Antonia Carla Testa’s name.
Hospitalization Rates and Predictors of Rehospitalization Among Individuals With Advanced Cancer in the Year After Diagnosis J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-29 Robin L. Whitney; Janice F. Bell; Daniel J. Tancredi; Patrick S. Romano; Richard J. Bold; Jill G. Joseph
Purpose Among individuals with advanced cancer, frequent hospitalization increasingly is viewed as a hallmark of poor-quality care. We examined hospitalization rates and individual- and hospital-level predictors of rehospitalization among individuals with advanced cancer in the year after diagnosis. Methods Individuals diagnosed with advanced breast, colorectal, non–small-cell lung, or pancreatic cancer from 2009 to 2012 (N = 25,032) were identified with data from the California Cancer Registry (CCR). After linkage with inpatient discharge data, multistate and log-linear Poisson regression models were used to calculate hospitalization rates and to model rehospitalization in the year after diagnosis, accounting for survival. Results In the year after diagnosis, 71% of individuals with advanced cancer were hospitalized, 16% had three or more hospitalizations, and 64% of hospitalizations originated in the emergency department. Rehospitalization rates were significantly associated with black non-Hispanic (incidence rate ratio [IRR], 1.29; 95% CI, 1.17 to 1.42) and Hispanic (IRR, 1.11; 95% CI, 1.03 to 1.20) race/ethnicity; public insurance (IRR, 1.37; 95% CI, 1.23 to 1.47) and no insurance (IRR, 1.17; 95% CI, 1.02 to 1.35); lower socioeconomic status quintiles (IRRs, 1.09 to 1.29); comorbidities (IRRs, 1.13 to 1.59); and pancreatic (IRR, 2.07; 95% CI, 1.95 to 2.20) and non–small-cell lung (IRR, 1.69; 95% CI, 1.54 to 1.86) cancers versus colorectal cancer. Rehospitalization rates were significantly lower after discharge from a hospital that had an outpatient palliative care program (IRR, 0.90; 95% CI, 0.83 to 0.97) and were higher after discharge from a for-profit hospital (IRR, 1.33; 95% CI, 1.14 to 1.56). Conclusion Individuals with advanced cancer experience a heavy burden of hospitalization in the year after diagnosis. Efforts to reduce hospitalization and provide care congruent with patient preferences might target individuals at higher risk. Future work might explore access to palliative care in the community and related health care use among individuals with advanced cancer.
Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation as Alternative to Matched Sibling or Unrelated Donor Transplantation for Hodgkin Lymphoma: A Registry Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-28 Carmen Martínez; Jorge Gayoso; Carmen Canals; Hervé Finel; Karl Peggs; Alida Dominietto; Luca Castagna; Boris Afanasyev; Stephen Robinson; Didier Blaise; Paolo Corradini; Maija Itälä-Remes; Arancha Bermúdez; Edouard Forcade; Domenico Russo; Michael Potter; Grant McQuaker; Ibrahim Yakoub-Agha; Christof Scheid; Adrian Bloor; Silvia Montoto; Peter Dreger; Anna Sureda; on behalf of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation
Purpose To compare the outcome of patients with Hodgkin lymphoma who received post-transplantation cyclophosphamide–based haploidentical (HAPLO) allogeneic hematopoietic cell transplantation with the outcome of patients who received conventional HLA-matched sibling donor (SIB) and HLA-matched unrelated donor (MUD). Patients and Methods We retrospectively evaluated 709 adult patients with Hodgkin lymphoma who were registered in the European Society for Blood and Marrow Transplantation database who received HAPLO (n = 98), SIB (n = 338), or MUD (n = 273) transplantation. Results Median follow-up of survivors was 29 months. No differences were observed between groups in the incidence of acute graft-versus-host disease (GVHD). HAPLO was associated with a lower risk of chronic GVHD (26%) compared with MUD (41%; P = .04). Cumulative incidence of nonrelapse mortality at 1 year was 17%, 13%, and 21% in HAPLO, SIB, and MUD, respectively, and corresponding 2-year cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. On multivariable analysis, relative to SIB, nonrelapse mortality was similar in HAPLO (P = .26) and higher in MUD (P = .003), and risk of relapse was lower in both HAPLO (P = .047) and MUD (P < .001). Two-year overall survival and progression-free survival were 67% and 43% for HAPLO, 71% and 38% for SIB, and 62% and 45% for MUD, respectively. There were no significant differences in overall survival or progression-free survival between HAPLO and SIB or MUD. The rate of the composite end point of extensive chronic GVHD and relapse-free survival was significantly better for HAPLO (40%) compared with SIB (28%; P = .049) and similar to MUD (38%; P = .59). Conclusion Post-transplantation cyclophosphamide–based HAPLO transplantation results in similar survival outcomes compared with SIB and MUD, which confirms its suitability when no conventional donor is available. Our results also suggest that HAPLO results in a lower risk of chronic GVHD than MUD transplantation.
Risk of Alzheimer’s Disease Among Senior Medicare Beneficiaries Treated With Androgen Deprivation Therapy for Prostate Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-25 Seo Hyon Baik; Fabricio Sampaio Peres Kury; Clement Joseph McDonald
Purpose To assess the relative risk of Alzheimer’s disease (AD) among patients with prostate cancer who received androgen deprivation therapy (ADT), after adjustment for other cancer therapies. Methods Data from demographics, survival, diagnoses codes, procedure codes, and other information about beneficiaries age 67 years or older in the Medicare claims database was assessed to determine the unadjusted and adjusted risks of AD and of dementia from ADT. The prespecified survival analysis method was competing risk regression. Results Of the 1.2 million fee-for-service Medicare beneficiaries who developed prostate cancer in 2001 to 2014, 35% received ADT. Of these, 109,815 (8.9%) and 223,765 (18.8%) developed AD and dementia, respectively, and 26% to 33% died without either outcome. Unadjusted rates of AD and all-cause mortality per 1,000 patient-years were higher among ADT recipients; the unadjusted rates of AD were 17.0 and 15.5 per 1,000 person-years in recipients and nonrecipients, respectively, and the unadjusted rates of all-cause mortality were 73.0 and 51.6 per 1,000 person-years, respectively. The unadjusted rates for dementia in ADT recipients versus nonrecipients were 38.5 and 32.9, respectively, and the unadjusted rates of mortality were 60.2 versus 40.4, respectively. However, after analysis was adjusted for other cancer therapies and other covariates, patients with ADT treatment had no increased risk of AD (subdistribution hazard ratio [SHR], 0.98; 95% CI, 0.97 to 0.99) and had only a miniscule (1%) risk of dementia (SHR, 1.01; 95% CI, 1.01 to 1.02); patients treated with ADT were more likely to die before progression to AD (SHR, 1.24; 95% CI, 1.23 to 1.24) or dementia (SHR, 1.26; 95% CI, 1.25 to 1.26). The risks of AD and dementia were not associated with duration of ADT (ie, no dose effect). Other secondary analyses confirmed these results. Conclusion These data suggest that ADT treatment has no hazard for AD and no meaningful hazard for dementia among men age 67 years or older who are enrolled in Medicare.
Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-25 Dirk Schadendorf; Jedd D. Wolchok; F. Stephen Hodi; Vanna Chiarion-Sileni; Rene Gonzalez; Piotr Rutkowski; Jean-Jacques Grob; C. Lance Cowey; Christopher D. Lao; Jason Chesney; Caroline Robert; Kenneth Grossmann; David McDermott; Dana Walker; Rafia Bhore; James Larkin; Michael A. Postow
Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs (P = .97). Median overall survival had not been reached in either group (P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.
Osimertinib As First-Line Treatment of EGFR Mutation–Positive Advanced Non–Small-Cell Lung Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-25 Suresh S. Ramalingam; James C.-H. Yang; Chee Khoon Lee; Takayasu Kurata; Dong-Wan Kim; Thomas John; Naoyuki Nogami; Yuichiro Ohe; Helen Mann; Yuri Rukazenkov; Serban Ghiorghiu; Daniel Stetson; Aleksandra Markovets; J. Carl Barrett; Kenneth S. Thress; Pasi A. Jänne
Purpose The Osimertinib First Time in Patients Ascending Dose (AURA) study (ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] –tyrosine kinase inhibitor selective for EGFR–tyrosine kinase inhibitor sensitizing [EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non–small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator-assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma samples were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. Results At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median PFS time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected. Conclusion Osimertinib demonstrated a robust ORR and prolonged PFS in treatment-naïve patients with EGFRm advanced NSCLC. There was no evidence of acquired EGFR T790M mutation in postprogression plasma samples.
Androgen Deprivation Therapy and Dementia: New Opportunities and Challenges in the Big-Data Era J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-25 Kevin T. Nead
Androgen deprivation therapy (ADT) extends life for appropriately selected patients diagnosed with prostate cancer.1 Level-1 evidence supports this survival benefit in a wide breadth of clinical scenarios, which leads to high rates of ADT use globally.2 A complete understanding of the adverse effects of this therapy is paramount to permit informed decision making and patient selection. As a part of this effort, a body of literature developed that supported a potential association between ADT and adverse cognitive function.3,4 Subsequently, two research articles were published that used an electronic medical record (EMR)–based informatics approach to support a link between ADT and dementia in large, multi-institutional analyses.5,6 However, not all studies have supported this association.7 Given the widespread use and effectiveness of ADT, investigations that replicate and assess causality of an association between ADT and dementia are critical before changes in patient care are considered.
Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1–Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-24 Chiun Hsu; Se-Hoon Lee; Samuel Ejadi; Caroline Even; Roger B. Cohen; Christophe Le Tourneau; Janice M. Mehnert; Alain Algazi; Emilie M.J. van Brummelen; Sanatan Saraf; Pradeep Thanigaimani; Jonathan D. Cheng; Aaron R. Hansen
Purpose To establish the safety profile and antitumor activity of the anti–programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.
Human Papillomavirus Vaccination Rates in Young Cancer Survivors J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-24 James L. Klosky; Melissa M. Hudson; Yanjun Chen; James A. Connelly; Karen Wasilewski-Masker; Can-Lan Sun; Liton Francisco; Laura Gustafson; Kathryn M. Russell; Gina Sabbatini; Jessica S. Flynn; Jocelyn M. York; Anna R. Giuliano; Leslie L. Robison; F. Lennie Wong; Smita Bhatia; Wendy Landier
Purpose Cancer survivors are at high risk for human papillomavirus (HPV)-related morbidities; we estimated the prevalence of HPV vaccine initiation in cancer survivors versus the US population and examined predictors of noninitiation. Methods Participants included 982 cancer survivors (9 to 26 years of age; 1 to 5 years postcompletion of therapy); we assessed HPV vaccine initiation, sociodemographic and clinical characteristics, and vaccine-specific health beliefs; age-, sex-, and year-matched US population comparisons were from the National Immunization Survey-Teen and the National Health Interview Survey (2012-2015). Results The mean age at the time of the study was 16.3 ± 4.7 years; the mean time off therapy was 2.7 ± 1.2 years; participants were 55% male and 66% non-Hispanic white; 59% had leukemia/lymphoma. Vaccine initiation rates were significantly lower in cancer survivors versus the general population (23.8%; 95% CI, 20.6% to 27.0% v 40.5%; 95% CI, 40.2% to 40.7%; P < .001); survivors were more likely to be HPV vaccine–naïve than general population peers (odds ratio [OR], 1.72; 95% CI, 1.41 to 2.09; P < .001). Initiation in adolescent survivors (ages 13 to 17 years) was 22.0% (95% CI, 17.3% to 26.7%), significantly lower than population peers (42.5%; 95% CI, 42.2% to 42.8%; P < .001). Initiation in young adult survivors and peers (ages 18 to 26 years) was comparably low (25.3%; 95% CI, 20.9% to 29.7% v 24.2%; 95% CI, 23.6% to 24.9%). Predictors of noninitiation included lack of provider recommendation (OR, 10.8; 95% CI, 6.5 to 18.0; P < .001), survivors’ perceived lack of insurance coverage for HPV vaccine (OR, 6.6; 95% CI, 3.9 to 11.0; P < .001), male sex (OR, 2.9; 95% CI, 1.7 to 4.8; P < .001), endorsement of vaccine-related barriers (OR, 2.7; 95% CI, 1.6 to 4.6; P < .001), and younger age (9 to 12 years; OR, 3.7; 95% CI, 1.8-7.6; P < .001; comparison, 13 to 17 years). Conclusion HPV vaccine initiation rates in cancer survivors are low. Lack of provider recommendation and barriers to vaccine receipt should be targeted in vaccine promotion efforts.
Improving Outcomes in High-Risk Myelodysplasia: Festina Lente J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Charles Craddock
The myelodysplastic syndromes (MDS) represent a compendious group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in peripheral blood cytopenias and a significant risk of transformation to acute myeloid leukemia (AML). The degree of cytopenia, blast percentage, and presentation karyotype permit identification of patients with high-risk MDS whose outcome is particularly poor. Targeted mutational analysis has transformed our understanding of the pathogenesis of MDS and, at the same time, provided the tools for preliminary analyses of clonal structure. Acquired abnormalities in classes of genes determining chromatin structure, including mutations in DNMT3A, TET2, IDH1, and IDH2 (which influence CpG island methylation status) and EZH2 and ASZL1 (which contribute to the control of histone acetylation) are commonly observed in MDS and likely contribute to disease pathogenesis.1
Converging on the Value of Value Frameworks J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Lowell E. Schnipper; Richard L. Schilsky
The relentless increase in health care costs has been difficult to control and is widely believed to be approaching a tipping point that threatens the economic well-being of many nations and their citizens. Although cancer represents only a fraction of total health care expenditures, economists are predicting an increase in the costs of cancer care in the United States from $120 billion in 2010 to $158 billion in 2020.1 Many factors contribute to this increase including larger numbers of patients with cancer, which is a reflection of the aging population; higher costs of hospitalizations and procedures; and longer survival while on treatment.1 The steepest increments in cost are projected to be related to the cost of cancer drugs.2
In Accordance With Our Best Estimates J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Michael A. Bookman
In the article accompanying this editorial, Janowitz et al1 describe a new model for estimating glomerular filtration rate (GFR) in patients with cancer. The authors are to be congratulated for obtaining access to a large data set, which included objective measurement of GFR using chromium-51 (51Cr)–EDTA. Prior reports have compared different methods of estimating creatinine clearance (CrCl) without an actual standardized independent measurement of GFR, and it has been difficult to determine which method should be used for renal-based drug dosing. Other reports have compared estimated CrCl with measured CrCl, on the basis of a 24-hour urine collection. However, measured urine CrCl is still only an approximation of GFR, and the same physiologic factors that can affect serum levels of creatinine can alter the measured CrCl, which may not accurately reflect GFR.
Changing the Natural History of Non–Small-Cell Lung Cancer Through Upfront Programmed Death Protein 1/Programmed Death-Ligand 1 Blockade J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Daniel S.W. Tan
Lung cancer remains the most frequent cause of cancer-related mortality.1 In the last decade, significant advances have been made in the management of metastatic non–small-cell lung cancer (NSCLC), ranging from stratification into multiple therapeutically relevant genomic subsets (eg, EGFR and ALK)2,3 to the expanding role of immune checkpoint inhibitors.4 Currently, three immune checkpoint inhibitors have gained FDA approval for treatment of advanced NSCLC: nivolumab, pembrolizumab, and atezolizumab.5-7 Although these indications were based on positive phase III trials demonstrating significant overall survival (OS) benefit when compared with docetaxel chemotherapy in the second- and third-line settings, they differ in their programmed death-ligand 1 (PDL1) patient–selection strategy. Although PDL1 status was evaluated in all three trials and was consistently shown to enrich for patients who have a higher likelihood of benefit, label indications for nivolumab and atezolizumab do not stipulate the need for selection on the basis of PDL1 status, whereas use of pembrolizumab is restricted to patients with a tumor proportion score (TPS) ≥ 1%. There has since been continued enthusiasm in targeting the programmed death protein 1/PDL1 axis, with the initiation of several phase II and III trials using a range of patient-enrichment and combinatorial strategies; such trials are poised to define a new therapeutic bar in treatment-naïve NSCLC.
Pediatric Palliative Oncology: Bridging Silos of Care Through an Embedded Model J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Erica C. Kaye; Jennifer M. Snaman; Justin N. Baker
Over the past decade, a growing partnership between the fields of oncology and palliative care (PC) has emerged, giving rise to the nascent discipline of palliative oncology.1,2 The relatively recent finding that patients with cancer who receive early integration of PC experience improved survival and quality of life (QOL)3 has stimulated a wave of research corroborating the beneficial impact of PC integration within adult cancer care paradigms.4-13
Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117 J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Mikkael A. Sekeres; Megan Othus; Alan F. List; Olatoyosi Odenike; Richard M. Stone; Steven D. Gore; Mark R. Litzow; Rena Buckstein; Min Fang; Diane Roulston; Clara D. Bloomfield; Anna Moseley; Aziz Nazha; Yanming Zhang; Mario R. Velasco; Rakesh Gaur; Ehab Atallah; Eyal C. Attar; Elina K. Cook; Alyssa H. Cull; Michael J. Rauh; Frederick R. Appelbaum; Harry P. Erba
Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications (P < .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide (P = .14 v azacitidine), and 27% for azacitidine plus vorinostat (P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.
Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in Induction Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Je-Hwan Lee; Hawk Kim; Young-Don Joo; Won-Sik Lee; Sung Hwa Bae; Dae Young Zang; Jihyun Kwon; Min Kyoung Kim; Junglim Lee; Gyeong Won Lee; Jung-Hee Lee; Yunsuk Choi; Dae-Young Kim; Eun-Hye Hur; Sung-Nam Lim; Sang-Min Lee; Hun Mo Ryoo; Hyo Jung Kim; Myung Soo Hyun; Kyoo-Hyung Lee; for the Cooperative Study Group A for Hematology
Purpose We compared two induction regimens, idarubicin (12 mg/m2/d for 3 days) versus high-dose daunorubicin (90 mg/m2/d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML). Patients and Methods A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m2/d for 7 days). Results Complete remission (CR) was induced in 232 patients (77.6%), with no difference in CR rates between the AI and AD arms (80.5% v 74.7%, respectively; P = .224). At a median follow-up time of 34.9 months, survival and relapse rates did not differ between the AI and AD arms (4-year overall survival, 51.1% v 54.7%, respectively; P = .756; cumulative incidence of relapse, 35.2% v 25.1%, respectively; P = .194; event-free survival, 45.5% v 50.8%, respectively; P = .772). Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3 internal tandem duplication (ITD) mutation were significantly different (AI v AD: median overall survival, 15.5 months v not reached, respectively; P = .030; event-free survival, 11.9 months v not reached, respectively; P = .028). Conclusion This phase III trial comparing idarubicin with high-dose daunorubicin did not find significant differences in CR rates, relapse, and survival. Significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation.
Do the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology Magnitude of Clinical Benefit Scale Measure the Same Construct of Clinical Benefit? J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Sierra Cheng; Erica J. McDonald; Matthew C. Cheung; Vanessa S. Arciero; Mahin Qureshi; Di Jiang; Doreen Ezeife; Mona Sabharwal; Alexandra Chambers; Dolly Han; Natasha Leighl; Kelley-Anne Sabarre; Kelvin K.W. Chan
Purpose Whether the ASCO Value Framework and the European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) measure similar constructs of clinical benefit is unclear. It is also unclear how they relate to quality-adjusted life-years (QALYs) and funding recommendations in the United Kingdom and Canada. Methods Randomized clinical trials of oncology drug approvals by the US Food and Drug Administration, European Medicines Agency, and Health Canada between 2006 and August 2015 were identified and scored using the ASCO version 1 (v1) framework, ASCO version 2 (v2) framework, and ESMO-MCBS by at least two independent reviewers. Spearman correlation coefficients were calculated to assess construct (between frameworks) and criterion validity (against QALYs from the National Institute for Health and Care Excellence [NICE] and the pan-Canadian Oncology Drug Review [pCODR]). Associations between scores and NICE/pCODR recommendations were examined. Inter-rater reliability was assessed using intraclass correlation coefficients. Results From 109 included randomized clinical trials, 108 ASCOv1, 111 ASCOv2, and 83 ESMO scores were determined. Correlation coefficients for ASCOv1 versus ESMO, ASCOv2 versus ESMO, and ASCOv1 versus ASCOv2 were 0.36 (95% CI, 0.15 to 0.54), 0.17 (95% CI, −0.06 to 0.37), and 0.50 (95% CI, 0.35 to 0.63), respectively. Compared with NICE QALYs, correlation coefficients were 0.45 (ASCOv1), 0.53 (ASCOv2), and 0.46 (ESMO); with pCODR QALYs, coefficients were 0.19 (ASCOv1), 0.20 (ASCOv2), and 0.36 (ESMO). None of the frameworks were significantly associated with NICE/pCODR recommendations. Inter-rater reliability was good for all frameworks. Conclusion The weak-to-moderate correlations of the ASCO frameworks with the ESMO-MCBS, as well as their correlations with QALYs and with NICE/pCODR funding recommendations, suggest different constructs of clinical benefit measured. Construct convergent validity with the ESMO-MCBS did not increase with the updated ASCO framework.
Regionalization and Outcomes of Lung Cancer Surgery in Ontario, Canada J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Anna M. Bendzsak; Nancy N. Baxter; Gail E. Darling; Peter C. Austin; David R. Urbach
Purpose Regionalization of complex surgery to high-volume hospitals has been advocated based on cross-sectional volume-outcome studies. In April 2007, the agency overseeing cancer care in Ontario, Canada, implemented a policy to regionalize lung cancer surgery at 14 designated hospitals, enforced by economic incentives and penalties. We studied the effects of implementation of this policy. Methods Using administrative health data, we used interrupted time series models to analyze the immediate and delayed effects of implementation of the policy on the distribution of lung cancer surgery among hospitals, surgical outcomes, and health services use. Results From 2004 to 2012, 16,641 patients underwent surgery for lung cancer. The proportion of operations performed in designated hospitals increased from 71% to 89% after the policy was implemented. Although operative mortality decreased from 4.1% to 2.9% (adjusted odds ratio, 0.68; 95% CI, 0.58 to 0.81; P < .001), the reduction was due to a preexisting declining trend in mortality. In contrast, in the years after implementation of the policy, length of hospital stay decreased more than expected from the baseline trend by 7% per year (95% CI, 5% to 9%; P < .001), and the distance traveled by all patients to the hospital for surgery increased by 4% per year (95% CI, 0% to 8%; P = .03), neither of which were explained by preexisting trends. Analyses limited to patients ≥ 70 years of age demonstrated a reduction in operative mortality (odds ratio, 0.80 per year after regionalization; 95% CI, 0.67 to 0.95; P = .01). Conclusion A policy to regionalize lung cancer surgery in Ontario led to increased centralization of surgery services but was not independently associated with improvements in operative mortality. Improvements in length of stay and in operative mortality among elderly patients suggest areas where regionalization may be beneficial.
Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1–Selected Advanced Non–Small-Cell Lung Cancer (BIRCH) J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Solange Peters; Scott Gettinger; Melissa L. Johnson; Pasi A. Jänne; Marina C. Garassino; Daniel Christoph; Chee Keong Toh; Naiyer A. Rizvi; Jamie E. Chaft; Enric Carcereny Costa; Jyoti D. Patel; Laura Q.M. Chow; Marianna Koczywas; Cheryl Ho; Martin Früh; Michel van den Heuvel; Jeffrey Rothenstein; Martin Reck; Luis Paz-Ares; Frances A. Shepherd; Takayasu Kurata; Zhengrong Li; Jiaheng Qiu; Marcin Kowanetz; Simonetta Mocci; Geetha Shankar; Alan Sandler; Enriqueta Felip
Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non–small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1–expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility–assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility–assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1–selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.
Therapy of Advanced Non–Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Rebecca Suk Heist; Michael J. Guarino; Gregory Masters; W. Thomas Purcell; Alexander N. Starodub; Leora Horn; Ronald J. Scheff; Aditya Bardia; Wells A. Messersmith; Jordan Berlin; Allyson J. Ocean; Serengulam V. Govindan; Pius Maliakal; Boyd Mudenda; William A. Wegener; Robert M. Sharkey; David M. Goldenberg; D. Ross Camidge
Purpose Trop-2, expressed in most solid cancers, may be a target for antibody-drug conjugates (ADCs) in non–small-cell lung cancer (NSCLC). We studied sacituzumab govitecan (IMMU-132), a Trop-2 ADC, for the targeting of SN-38. Patients and Methods We evaluated IMMU-132 in a single-arm multicenter trial in patients with pretreated metastatic NSCLC who received either 8 or 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end points were safety and objective response rate (ORR). Progression-free survival and overall survival were secondary end points. Results Fifty-four patients were treated. In the response-assessable study population (n = 47), which had a median of three prior therapies (range, two to seven), the ORR was 19%; median response duration, 6.0 months (95% CI, 4.8 to 8.3 months); and clinical benefit rate (complete response + partial response + stable disease ≥ 4 months), 43%. ORR in the intention-to-treat (ITT) population was 17% (nine of 54). Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy. Median ITT progression-free survival was 5.2 months (95% CI, 3.2 to 7.1 months) and median ITT overall survival, 9.5 months (95% CI, 5.9 to 16.7 months). Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%). One patient developed a transient immune response, despite patients receiving a median of 10 doses. More than 90% of 26 assessable archival tumor specimens were highly positive (2+, 3+) for Trop-2 by immunohistochemistry, which suggests that Trop-2 is not a predictive biomarker for response. Conclusion IMMU-132 was well-tolerated and induced durable responses in heavily pretreated patients with metastatic NSCLC. This ADC should be studied further in this disease and in other patients with Trop-2–expressing tumors.
New Model for Estimating Glomerular Filtration Rate in Patients With Cancer J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Tobias Janowitz; Edward H. Williams; Andrea Marshall; Nicola Ainsworth; Peter B. Thomas; Stephen J. Sammut; Scott Shepherd; Jeff White; Patrick B. Mark; Andy G. Lynch; Duncan I. Jodrell; Simon Tavaré; Helena Earl
Purpose The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing; however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods We obtained data on age, sex, height, weight, serum creatinine concentrations, and results for GFR from chromium-51 (51Cr) EDTA excretion measurements (51Cr-EDTA GFR) from white patients ≥ 18 years of age with histologically confirmed cancer diagnoses at the Cambridge University Hospital NHS Trust, United Kingdom. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared with the estimated GFR (eGFR) from seven published models and our new model, using the statistics root-mean-squared-error (RMSE) and median residual and on an internal and external validation data set. We performed a comparison of carboplatin dosing accuracy on the basis of an absolute percentage error > 20%. Results Between August 2006 and January 2013, data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE, 15.00 mL/min; 95% CI, 14.12 to 16.00 mL/min) compared with all published models. Body surface area (BSA)–adjusted chronic kidney disease epidemiology (CKD-EPI) was the most accurate published model for eGFR (RMSE, 16.30 mL/min; 95% CI, 15.34 to 17.38 mL/min) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose absolute percentage error > 20% to 14.17% in contrast to 18.62% for the BSA-adjusted CKD-EPI and 25.51% for the Cockcroft-Gault formula. The results were externally validated. Conclusion In a large data set from patients with cancer, BSA-adjusted CKD-EPI is the most accurate published model to predict GFR. The new model improves this estimation and may present a new standard of care.
Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Xinwei Hua; Amanda I. Phipps; Andrea N. Burnett-Hartman; Scott V. Adams; Sheetal Hardikar; Stacey A. Cohen; Jonathan M. Kocarnik; Dennis J. Ahnen; Noralane M. Lindor; John A. Baron; Polly A. Newcomb
Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status (Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.
Efficacy of a Weight Loss Intervention for African American Breast Cancer Survivors J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Melinda Stolley; Patricia Sheean; Ben Gerber; Claudia Arroyo; Linda Schiffer; Anjishnu Banerjee; Alexis Visotcky; Giamila Fantuzzi; Desmona Strahan; Lauren Matthews; Roxanne Dakers; Cynthia Carridine-Andrews; Katya Seligman; Sparkle Springfield; Angela Odoms-Young; Susan Hong; Kent Hoskins; Virginia Kaklamani; Lisa Sharp
Purpose African American women with breast cancer have higher cancer-specific and overall mortality rates. Obesity is common among African American women and contributes to breast cancer progression and numerous chronic conditions. Weight loss interventions among breast cancer survivors positively affect weight, behavior, biomarkers, and psychosocial outcomes, yet few target African Americans. This article examines the effects of Moving Forward, a weight loss intervention for African American breast cancer survivors (AABCS) on weight, body composition, and behavior. Patients and Methods Early-stage (I-III) AABCS were randomly assigned to a 6-month interventionist-guided (n = 125) or self-guided (n = 121) weight loss program supporting behavioral changes to promote a 5% weight loss. Anthropometric, body composition, and behavioral data were collected at baseline, postintervention (6 months), and follow-up (12 months). Descriptive statistics and mixed models analyses assessed differences between groups over time. Results Mean (± standard deviation) age, and body mass index were 57.5 (± 10.1) years and 36.1 (± 6.2) kg/m2, respectively, and 82% had stage I or II breast cancer. Both groups lost weight. Mean and percentage of weight loss were greater in the guided versus self-guided group (at 6 months: 3.5 kg v 1.3kg; P < .001; 3.6% v 1.4%; P < .001, respectively; at 12 months: 2.7 kg v 1.6 kg; P < .05; 2.6% v 1.6%; P < .05, respectively); 44% in the guided group and 19% in the self-guided group met the 5% goal. Body composition and behavioral changes were also greater in the interventionist-guided group at both time points. Conclusion The study supports the efficacy of a community-based interventionist-guided weight loss program targeting AABCS. Although mean weight loss did not reach the targeted 5%, the mean loss of > 3% at 6 months is associated with improved health outcomes. Affordable, accessible health promotion programs represent a critical resource for AABCS.
Impact of 70-Gene Signature Use on Adjuvant Chemotherapy Decisions in Patients With Estrogen Receptor–Positive Early Breast Cancer: Results of a Prospective Cohort Study J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Anne Kuijer; Marieke Straver; Bianca den Dekker; Annelotte C.M. van Bommel; Sjoerd G. Elias; Carolien H. Smorenburg; Jelle Wesseling; Sabine C. Linn; Emiel J.Th. Rutgers; Sabine Siesling; Thijs van Dalen
Purpose Gene-expression profiles increasingly are used in addition to conventional prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in patients with estrogen receptor (ER) –positive, early-stage breast cancer without overt lymph node metastases. We aimed to assess the impact of a 70-gene signature (70-GS) test on CT decisions in patients with ER-positive, early-stage breast cancer. Patients and Methods In a prospective, observational, multicenter study in patients younger than 70 years old who had undergone surgery for ER-positive, early-stage breast cancer, physicians were asked whether they intended to administer adjuvant CT before deployment of the 70-GS test and after the test result was available. Results Between October 1, 2013, and December 31, 2015, 660 patients, treated in 33 hospitals, were enrolled. Fifty-one percent of patients had pT1cN0, BRII, HER2-Neu-negative breast cancer. On the basis of conventional clinicopathological characteristics, physicians recommended CT in 270 (41%) of the 660 patients and recommended withholding CT in 107 (16%) of the 660 patients. For the remaining 43% of patients, the physicians were unsure and unable to give advice before 70-GS testing. In patients for whom CT was initially recommended or not recommended, 56% and 59%, respectively, were assigned to a low-risk profile by the 70-GS (κ, 0.02; 95% CI, -0.08 to 0.11). After disclosure of the 70-GS test result, the preliminary advice was changed in 51% of patients who received a recommendation before testing; the definitive CT recommendation of the physician was in line with the 70-GS result in 96% of patients. Conclusion In this prospective, multicenter study in a selection of patients with ER-positive, early-stage breast cancer, 70-GS use changed the physician-intended recommendation to administer CT in half of the patients.
Quantitative Assessment of Early [18F]Sodium Fluoride Positron Emission Tomography/Computed Tomography Response to Treatment in Men With Metastatic Prostate Cancer to Bone J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Stephanie A. Harmon; Timothy Perk; Christie Lin; Jens Eickhoff; Peter L. Choyke; William L. Dahut; Andrea B. Apolo; John L. Humm; Steven M. Larson; Michael J. Morris; Glenn Liu; Robert Jeraj
Purpose [18F]Sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) is a promising radiotracer for quantitative assessment of bone metastases. This study assesses changes in early NaF PET/CT response measures in metastatic prostate cancer for correlation to clinical outcomes. Patients and Methods Fifty-six patients with metastatic castration-resistant prostate cancer (mCRPC) with osseous metastases had NaF PET/CT scans performed at baseline and after three cycles of chemotherapy (n = 16) or androgen receptor pathway inhibitors (n = 40). A novel technology, Quantitative Total Bone Imaging, was used for analysis. Global imaging metrics, including maximum standardized uptake value (SUVmax) and total functional burden (SUVtotal), were extracted from composite lesion–level statistics for each patient and tracked throughout treatment. Progression-free survival (PFS) was calculated as a composite end point of progressive events using conventional imaging and/or physician discretion of clinical benefit; NaF imaging was not used for clinical evaluation. Cox proportional hazards regression analyses were conducted between imaging metrics and PFS. Results Functional burden (SUVtotal) assessed midtreatment was the strongest univariable PFS predictor (hazard ratio, 1.97; 95% CI, 1.44 to 2.71; P < .001). Classification of patients based on changes in functional burden showed stronger correlation to PFS than did the change in number of lesions. Various global imaging metrics outperformed baseline clinical markers in predicting outcome, including SUVtotal and SUVmean. No differences in imaging response or PFS correlates were found for different treatment cohorts. Conclusion Quantitative total bone imaging enables comprehensive disease quantification on NaF PET/CT imaging, showing strong correlation to clinical outcomes. Total functional burden assessed after three cycles of hormonal therapy or chemotherapy was predictive of PFS for men with mCRPC. This supports ongoing development of NaF PET/CT–based imaging biomarkers in mCRPC to bone.
Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Ian Krop; Nofisat Ismaila; Fabrice Andre; Robert C. Bast; William Barlow; Deborah E. Collyar; M. Elizabeth Hammond; Nicole M. Kuderer; Minetta C. Liu; Robert G. Mennel; Catherine Van Poznak; Antonio C. Wolff; Vered Stearns
Purpose This focused update addresses the use of MammaPrint (Agendia, Irvine, CA) to guide decisions on the use of adjuvant systemic therapy. Methods ASCO uses a signals approach to facilitate guideline updates. For this focused update, the publication of the phase III randomized MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study to evaluate the MammaPrint assay in 6,693 women with early-stage breast cancer provided a signal. An expert panel reviewed the results of the MINDACT study along with other published literature on the MammaPrint assay to assess for evidence of clinical utility. Recommendations If a patient has hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint assay does not have clinical utility in such patients. If a patient has hormone receptor–positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node. The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with hormone receptor–positive, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of definitive data in these populations. Additional information can be found at www.asco.org/breast-cancer-guidelines and www.asco.org/guidelineswiki.
Aptitude; Mother's Day; Winter Beach J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Gregory A. Abel
My grandfather worked fast
Treatment of Early-Stage Hodgkin Lymphoma: Are We Just Shifting Morbidities? J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 John A. Vargo; Diane C. Ling; Sushil Beriwal
In their recent article in Journal of Clinical Oncology, André et al1 reported the final analysis of the European Organisation for Research and Treatment of Cancer H10 trial, which examined the role of using positron emission tomography (PET) response to guide de-escalation of therapy via the omission of radiotherapy in early-stage Hodgkin lymphoma. At 5 years, the progression-free survival rate for favorable-risk patients was 99% in PET-negative patients receiving radiotherapy versus 87% in PET-negative patients receiving chemotherapy alone (hazard ratio, 15.8; 95% CI, 3.8 to 66.1), far exceeding the predetermined noninferiority margin of 3.2. Despite this result, the authors concluded that “treatment with chemotherapy only is defensible in individual patients.”1(p1793) Why define a threshold for a noninferiority clinical trial design, only to disregard the clearly inferior results of the study in the discussion when this threshold is exceeded? Although, certainly, individual patients can achieve excellent outcomes with additional cycles of chemotherapy, this potentially misleading interpretation of the results can have strongly negative implications for patients in clinical practice. The increasing over-application of chemotherapy-alone treatment strategies in early-stage Hodgkin lymphoma in the past decade have led to a decline in overall survival for thousands of patients with Hodgkin lymphoma on a national level.2 Results from both the European Organisation for Research and Treatment of Cancer H10 and UK-RAPID trials highlight that even in favorable-risk, PET-negative Hodgkin lymphoma, the addition of radiotherapy adds a significant increase in progression-free survival.3 However, what is not highlighted from these trials is that both trials included additional cycles of chemotherapy, over an established standard of care for favorable-risk Hodgkin lymphoma, of two cycles of chemotherapy plus low-dose (20 Gy) involved-site radiotherapy.4 Increasing the number of cycles of chemotherapy and radiotherapy both carry risks of acute and chronic toxicities; ignoring the implication of additional cycles of chemotherapy on the risks of cardiopulmonary disease or second malignancy is not justified by the data.5 In the last decade, radiotherapy dose and volumes have significantly decreased (with involved-node radiotherapy used in H10; Fig 1), thereby decreasing toxicity risks.6 In a disease where overall survival approaches 100%, all of these factors count. We need to be cautious in trading radiotherapy for additional chemotherapy, while discounting the morbidity of increasing chemotherapy cycles and increased relapses requiring salvage bone marrow transplant.
Interim Fluorodeoxyglucose Positron Emission Tomography–Adapted Therapy Is Not an Efficient Approach to Improving Outcome in Early-Stage Hodgkin Lymphoma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Hugo J.A. Adams; Thomas C. Kwee
We read with interest the recent article in Journal of Clinical Oncology by André et al,1 which included 1,950 patients with early-stage favorable or unfavorable Hodgkin lymphoma who underwent interim fluorodeoxyglucose (FDG) positron emission tomography (PET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Depending on the interim FDG-PET results, patients were randomly assigned to continuation of ABVD therapy with involved-field radiotherapy (IFRT); intensified therapy with escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) and IFRT; or de-escalated therapy with ABVD monotherapy without IFRT. After two cycles of ABVD, interim FDG-PET was positive in 18.8% of patients (13.0% with a favorable and 22.4% with an unfavorable risk profile). Treatment de-escalation in interim FDG-PET–negative patients was considered infeasible because of the higher relapse rate in patients treated without IFRT in both the favorable and unfavorable Hodgkin lymphoma subgroups. Unfortunately, subgroup analyses in interim FDG-PET–positive patients was not performed “because of their presumed common poor prognosis.”1(p1787) The 5-year progression-free survival (PFS) rate was 77.4% in interim FDG-PET–positive patients treated with standard treatment, with 36 of 192 (18.8%) patients developing disease relapse during follow-up, whereas the 5-year PFS rate was 90.6% in interim FDG-PET–positive patients treated with escalated treatment, with 13 of 169 (7.7%) patients developing disease relapse during follow-up, resulting in a risk difference of 11.1%. André et al1 concluded that classic European Organisation for Research and Treatment of Cancer prognostic factors (eg, erythrocyte sedimentation rate, B symptoms, age, and bulky disease) lose clinical relevance in the era of FDG- PET–adapted therapy. They also concluded that interim FDG-PET allowed for early treatment adaptation, but only for treatment intensification in interim FDG-PET–positive patients, whereas a negative interim FDG-PET result was not considered appropriate for omission of IFRT.
On the Role of Interim Fluorine-18–Labeled Fluorodeoxyglucose Positron Emission Tomography in Early-Stage Favorable Hodgkin Lymphoma J. Clin. Oncol. (IF 24.008) Pub Date : 2017-08-20 Elif Hindié; Charles Mesguich; Paolo Zanotti-Fregonara
Patients with stages I and II Hodgkin lymphoma (HL) treated by doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy followed by radiotherapy have high cure rates, with progression-free survival (PFS) rates at 5 years of approximately 95% for favorable and 87% for unfavorable risk groups.1 An interim 18-fluorine–labeled fluorodeoxyglucose positron emission tomography (PET) scan performed early during chemotherapy may identify patients who need reduced or more intensive treatments. Good responders may avoid the toxicity and adverse effects of radiotherapy, whereas poor responders would benefit from treatment intensification.2 The potential of interim PET was tested in the H10 trial in patients ages 15 to 70 years with supradiaphragmatic stages I and II HL; these results were recently reported in Journal of Clinical Oncology by André et al.3 The study included 754 patients with favorable HL and 1,196 patients with unfavorable disease, according to the European Organisation for Research and Treatment of Cancer criteria. Our comment focuses on the group of patients with favorable HL.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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